Bleeding frequently is the result of injury to the vascular system. Such injury can be caused by pathophysiological conditions, physical, mechanical, and/or pharmacologic insult.
For example, tPA administration for myocardial infarct is known to cause bleeding. In fact, the administration of anticoagulant, antiplatelet, antithrombotic, and thrombolytic agents to treat infarct are generally known to result in risk of hemorrhage. Fatal intracerebral hemorrhage can be associated with using a combination of antithrombotic agents, including abciximab, in patients undergoing neurointerventional procedures, as reported by Qyreshi, et al., Stroke (2002) 33:1916-1919. Hemorrhagic ocular and orbital complications are known to be associated with the use of systemic thrombolytic agents, as reported by Chorich, et al., Ophthalmology (1998) 105:428-431. Hemorrhagic stroke (intracerebral hemorrhage) is primarily associated with arterial hypertension and amyloid angiopathy. Other causes include vascular malformations, intracranial aneurysms, arterial and venous thrombosis, coagulopathy, neoplastic, vasculitis, drug abuse, and trauma.
Bleeding can result from mechanical injury such as percutaneous coronary intervention, clot removal, etc. Moreover, primary percutaneous coronary intervention (PCI) for acute ST elevation myocardial infarction (STEMI) is co-treated with aspirin, clopidogrel, heparin and platelet glycoprotein IIb/IIIa inhibitors. However, heparin and glycoprotein IIb/IIIa inhibitors are associated with a high incidence of bleeding (Brodie, B. R., Catheterization and Cardiovascular Interventions (2008) 71:816-821).
Organ transplantation is associated with bleeding of the microvascular bed; indeed, ischemia/reperfusion injury is a related condition that results in bleeding.
Current fibrinolytic regimens involving concurrent use of tPA, aspirin and heparin is still limited by inadequate coronary reperfusion in up to 40% of patients and early thrombotic reocclusion in 5-10% patients (Bahit, M. C., et al., Cardiol. Special Ed. (2001) 7:49-55). Hence, there is a great need for an optimal antiplatelet agent that acts quickly without increasing the risk of bleeding. In addition, ideal agents would preserve vascular integrity and function, prevent inflammation damage, and improve metabolic tolerance to ischemia and enhance preconditioning type responses (Bahit, supra).
Moreover, needed in the art is a method of reducing bleeding or the risk of bleeding associated with physical, mechanical, or pharmacological injury.